Farren Briggs

Telemedicine in Prehospital Stroke Evaluation and Thrombolysis: Taking Stroke Treatment to the Doorstep

IMPORTANCE Mobile stroke treatment units (MSTUs) with on-site treatment teams that include a vascular neurologist can provide thrombolysis in the prehospital setting faster than treatment in the hospital. These units can be made more resource efficient if the need for an on-site neurologist can be eliminated by relying solely on telemedicine for physician presence. OBJECTIVE To test whether telemedicine is reliable and remote physician presence is adequate for acute stroke treatment using an MSTU. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study conducted between July 18 and November 1, 2014. The dates of the study analysis were November 1, 2014, to March 30, 2015. The setting was a community-based study assessing telemedicine success of the MSTU in Cleveland, Ohio. Participants were the first 100 residents of Cleveland who had an acute onset of stroke-like symptoms between 8 am and 8 pm and were evaluated by the MSTU after the implementation of the MSTU program at the Cleveland Clinic. A vascular neurologist evaluated the first 100 patients via telemedicine, and a neuroradiologist remotely assessed images obtained by mobile computed tomography (CT). Data were entered into the medical record and a prospective registry. MAIN OUTCOMES AND MEASURES The study compared the evaluation and treatment of patients on the MSTU with a control group of patients brought to the emergency department via ambulance during the same year. Process times were measured from the time the patient entered the door of the MSTU or emergency department, and any problems encountered during his or her evaluation were recorded. RESULTS Ninety-nine of 100 patients were evaluated successfully. The median duration of telemedicine evaluation was 20 minutes (interquartile range [IQR], 14-27 minutes). One connection failure was due to crew error, and the patient was transported to the nearest emergency department. There were 6 telemedicine disconnections, none of which lasted longer than 60 seconds or affected clinical care. Times from the door to CT completion (13 minutes [IQR, 9-21 minutes]) and from the door to intravenous thrombolysis (32 minutes [IQR, 24-47 minutes]) were significantly shorter in the MSTU group compared with the control group (18 minutes [IQR, 12-26 minutes] and 58 minutes [IQR, 53-68 minutes], respectively). Times to CT interpretation did not differ significantly between the groups. CONCLUSIONS AND RELEVANCE An MSTU using telemedicine is feasible, with a low rate of technical failure, and may provide an avenue for reducing the high cost of such systems.

Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants.

Background: Tobacco smoke is an established risk factor for multiple sclerosis (MS). We hypothesized that variation in genes involved in metabolism of tobacco smoke constituents may modify MS risk in smokers. Methods: A three-stage gene-environment investigation was conducted for NAT1, NAT2, and GSTP1 variants. The discovery analysis was conducted among 1588 white MS cases and controls from the Kaiser Permanente Northern California Region HealthPlan (Kaiser). The replication analysis was carried out in 988 white MS cases and controls from Sweden. Results: Tobacco smoke exposure at the age of 20 years was associated with greater MS risk in both data sets (in Kaiser, odds ratio [OR] = 1.51 [95% confidence interval (CI) = 1.17–1.93]; in Sweden, OR = 1.35 [1.04–1.74]). A total of 42 NAT1 variants showed evidence for interaction with tobacco smoke exposure (Pcorrected < 0.05). Genotypes for 41 NAT1 single nucleotide polymorphisms (SNPs) were studied in the replication data set. A variant (rs7388368C>A) within a dense transcription factor-binding region showed evidence for interaction (Kaiser, OR for interaction = 1.75 [95% CI = 1.19–2.56]; Sweden, OR = 1.62 [1.05–2.49]). Tobacco smoke exposure was associated with MS risk among rs7388368A carriers only; homozygote individuals had the highest risk (A/A, OR = 5.17 [95% CI = 2.17–12.33]). Conclusions: We conducted a three-stage analysis using two population-based case-control datasets that consisted of a discovery population, a replication population, and a pooled analysis. NAT1 emerged as a genetic effect modifier of tobacco smoke exposure in MS susceptibility.

A Mobile Stroke Treatment Unit for Field Triage of Patients for Intraarterial Revascularization Therapy.

Favorable outcomes in intraarterial therapy (IAT) for acute ischemic stroke (AIS) are related to early vessel recanalization. The mobile stroke treatment unit (MSTU) is an on‐site, prehospital, treatment team, laboratory, and CT scanner that reduces time to treatment for intravenous thrombolysis and may also shorten time to IAT.

Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies

Objective: We investigated the association between 52 risk variants identified through genome-wide association studies and disease severity in multiple sclerosis (MS). Methods: Ten unique MS case data sets were analyzed. The Multiple Sclerosis Severity Score (MSSS) was calculated using the Expanded Disability Status Scale at study entry and disease duration. MSSS was considered as a continuous variable and as 2 dichotomous variables (median and extreme ends; MSSS of ≤5 vs >5 and MSSS of <2.5 vs ≥7.5, respectively). Single nucleotide polymorphisms (SNPs) were examined individually and as both combined weighted genetic risk score (wGRS) and unweighted genetic risk score (GRS) for association with disease severity. Random-effects meta-analyses were conducted and adjusted for cohort, sex, age at onset, and HLA-DRB1*15:01. Results: A total of 7,125 MS cases were analyzed. The wGRS and GRS were not strongly associated with disease severity after accounting for cohort, sex, age at onset, and HLA-DRB1*15:01. After restricting analyses to cases with disease duration ≥10 years, associations were null (p value ≥0.05). No SNP was associated with disease severity after adjusting for multiple testing. Conclusions: The largest meta-analysis of established MS genetic risk variants and disease severity, to date, was performed. Results suggest that the investigated MS genetic risk variants are not associated with MSSS, even after controlling for potential confounders. Further research in large cohorts is needed to identify genetic determinants of disease severity using sensitive clinical and MRI measures, which are critical to understanding disease mechanisms and guiding development of effective treatments.

Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12 566 individuals

The primary genetic risk factor in multiple sclerosis (MS) is the HLA-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has yet to be elucidated. Several lines of evidence support a role for neuroendocrine system involvement in autoimmunity which may, in part, be genetically determined. Here, we comprehensively investigated variation within eight candidate hypothalamic-pituitary-adrenal (HPA) axis genes and susceptibility to MS. A total of 326 SNPs were investigated in a discovery dataset of 1343 MS cases and 1379 healthy controls of European ancestry using a multi-analytical strategy. Random Forests, a supervised machine-learning algorithm, identified eight intronic SNPs within the corticotrophin-releasing hormone receptor 1 or CRHR1 locus on 17q21.31 as important predictors of MS. On the basis of univariate analyses, six CRHR1 variants were associated with decreased risk for disease following a conservative correction for multiple tests. Independent replication was observed for CRHR1 in a large meta-analysis comprising 2624 MS cases and 7220 healthy controls of European ancestry. Results from a combined meta-analysis of all 3967 MS cases and 8599 controls provide strong evidence for the involvement of CRHR1 in MS. The strongest association was observed for rs242936 (OR = 0.82, 95% CI = 0.74-0.90, P = 9.7 × 10(-5)). Replicated CRHR1 variants appear to exist on a single associated haplotype. Further investigation of mechanisms involved in HPA axis regulation and response to stress in MS pathogenesis is warranted.

Reduction in time to treatment in prehospital telemedicine evaluation and thrombolysis

Objective: To compare the times to evaluation and thrombolytic treatment of patients treated with a telemedicine-enabled mobile stroke treatment unit (MSTU) vs those among patients brought to the emergency department (ED) via a traditional ambulance. Methods: We implemented a MSTU with telemedicine at our institution starting July 18, 2014. A vascular neurologist evaluated each patient via telemedicine and a neuroradiologist and vascular neurologist remotely assessed images obtained by the MSTU CT. Data were entered in a prospective registry. The evaluation and treatment of the first 100 MSTU patients (July 18, 2014–November 1, 2014) was compared to a control group of 53 patients brought to the ED via a traditional ambulance in 2014. Times were expressed as medians with their interquartile ranges. Results: Patient and stroke severity characteristics were similar between 100 MSTU and 53 ED control patients (initial NIH Stroke Scale score 6 vs 7, p = 0.679). There was a significant reduction of median alarm-to-CT scan completion times (33 minutes MSTU vs 56 minutes controls, p < 0.0001), median alarm-to-thrombolysis times (55.5 minutes MSTU vs 94 minutes controls, p < 0.0001), median door-to-thrombolysis times (31.5 minutes MSTU vs 58 minutes controls, p = 0.0012), and symptom-onset-to-thrombolysis times (97 minutes MSTU vs 122.5 minutes controls, p = 0.0485). Sixteen patients evaluated on MSTU received thrombolysis, 25% of whom received it within 60 minutes of symptom onset. Conclusion: Compared with the traditional ambulance model, telemedicine-enabled ambulance-based thrombolysis resulted in significantly decreased time to imaging and treatment.

Smokers with MS have greater decrements in quality of life and disability than non-smokers

Background: Tobacco smoke plays a pathogenic role in multiple sclerosis (MS) and may accelerate disease progression, yet, some people with MS continue to smoke after disease onset. The average smoker reports diminished health-related quality of life (HRQOL) across many populations. Objectives: To describe the relationships between smoking status and HRQOL, disease activity, and global disability in a US population with MS. Methods: We compared smokers to non-smokers in 950 responders to the Spring 2014 update survey completed by North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants. HRQOL was assessed using Short Form-12 version 2 (SF-12v2), disease activity was investigated using eight Performance Scales (PS) and three Functionality Scales (FS). Global disability was evaluated using Patient Determined Disease Steps (PDDS) and an item response theory (IRT) summed score based on the PS and FS. Results: Smokers had lower HRQOL (p < 0.0001), reported more disease activity (p < 0.05) and greater deficits in all PS and FS (p = 6 × 10−7 to 0.05), except mobility. Smokers and non-smokers did not differ by PDDS but had substantially greater IRT global disability (p = 2 × 10−7). Conclusion: Active smoking is meaningfully associated with deficits across multiple domains in people with MS and adds to the growing literature of the need for MS-tailored smoking cessation programs.

Heterogeneous depression trajectories in multiple sclerosis patients

BACKGROUND Trajectories of depression over time may be heterogeneous in Multiple Sclerosis (MS) patients. Describing these trajectories will help clinicians understand better the progression of depression in MS patients to aid in patient care decisions. METHODS Latent class growth analysis (LCGA) was applied to 3507 MS patients using an electronic health records (EHR) data base to identify subgroups of MS patients based on self-reported depression screening (PHQ-9). Latent trajectory classes were used for group comparisons based on baseline clinical characteristics. RESULTS Three subgroups were found characterized by high (10.0% [of participants]), wavering above and below moderate (26.2%) and low and variable (63.8%) depression level trajectories. The subpopulation trajectories, respectively, were also characterized by high, moderate and low MS disability at baseline. In contrast, the overall average trajectory was slightly declining and below the moderate depression threshold. CONCLUSION The LCGA approach described in this paper and applied to MS patients provides a template for improved use of an EHR data base for understanding heterogeneous depression screening trajectories. Clinicians may use such information to more closely monitor patients that are expected to maintain high or unstable depression levels.

Feasibility study for remote assessment of cognitive function in multiple sclerosis

BACKGROUND Cognitive impairment is common in multiple sclerosis (MS), and affects employment and quality of life. Large studies are needed to identify risk factors for cognitive decline. Currently, a MS-validated remote assessment for cognitive function does not exist. Studies to determine feasibility of large remote cognitive function investigations in MS have not been published. OBJECTIVE To determine whether MS patients would participate in remote cognitive studies. We utilized the Modified Telephone Interview for Cognitive Status (TICS-M), a previously validated phone assessment for cognitive function in healthy elderly populations to detect mild cognitive impairment. We identified factors that influenced participation rates. We investigated the relationship between MS risk factors and TICS-M score in cases, and score differences between cases and control individuals. METHODS The TICS-M was administered to MS cases and controls. Linear and logistic regression models were utilized. RESULTS 11.5% of eligible study participants did not participate in cognitive testing. MS cases, females and individuals with lower educational status were more likely to refuse (p<0.001). Cases who did complete testing did not differ in terms of perceived cognitive deficit compared to cases that did participate. More severe disease, smoking, and being male were associated with a lower TICS-M score among cases (p<0.001). The TICS-M score was significantly lower in cases compared to controls (p=0.007). CONCLUSIONS Our results demonstrate convincingly that a remotely administered cognitive assessment is quite feasible for conducting large epidemiologic studies in MS, and lay the much needed foundation for future work that will utilize MS-validated cognitive measures.

Pathway Analysis of Genome-wide Association Study in Childhood Leukemia among Hispanics

Background: The incidence of acute lymphoblastic leukemia (ALL) is nearly 20% higher among Hispanics than non-Hispanic Whites. Previous studies have shown evidence for association between risk of ALL and variation within IKZF1, ARID5B, CEBPE, CDKN2A, GATA3, and BM1-PIP4K2A genes. However, variants identified only account for <10% of the genetic risk of ALL. Methods: We applied pathway-based analyses to genome-wide association study (GWAS) data from the California Childhood Leukemia Study to determine whether different biologic pathways were overrepresented in childhood ALL and major ALL subtypes. Furthermore, we applied causal inference and data reduction methods to prioritize candidate genes within each identified overrepresented pathway, while accounting for correlation among SNPs. Results: Pathway analysis results indicate that different ALL subtypes may involve distinct biologic mechanisms. Focal adhesion is a shared mechanism across the different disease subtypes. For ALL, the top five overrepresented Kyoto Encyclopedia of Genes and Genomes pathways include axon guidance, protein digestion and absorption, melanogenesis, leukocyte transendothelial migration, and focal adhesion (PFDR < 0.05). Notably, these pathways are connected to downstream MAPK or Wnt signaling pathways which have been linked to B-cell malignancies. Several candidate genes for ALL, such as COL6A6 and COL5A1, were identified through targeted maximum likelihood estimation. Conclusions: This is the first study to show distinct biologic pathways are overrepresented in different ALL subtypes using pathway-based approaches, and identified potential gene candidates using causal inference methods. Impact: The findings demonstrate that newly developed bioinformatics tools and causal inference methods can provide insights to furthering our understanding of the pathogenesis of leukemia. Cancer Epidemiol Biomarkers Prev; 25(5); 815–22. ©2016 AACR.